The immediate goal of this proposal is to elucidate the role of calcium/ calmodulin-activated calcineurin phosphatase in cell signaling. Our long term goal is to define the regulation and function among interplays of calcium signaling networks. Here, we will investigate the role of calcineurin phosphatase in the beta-adrenergic receptor signaling pathways. Calcineurin phosphatase is a holoenzyme composes of a catalytic calcineurin A (CnA) subunit, a regulatory calcineurin B subunit and calmodulin. Beta-adrenergic receptors are seven transmembrane receptors belong to the G protein coupled receptor (GPCR) superfamily. Physiologically, the beta-adrenergic receptor signaling pathways play a role in lipid homeostasis and hemodynamic regulation. Our recent data have indicated that CnA-beta contributes to lipid homeostasis and hemodynamics via the beta-adrenergic receptor signaling pathways. Mechanistically, ablation of CnA-beta in mouse embryonic fibroblasts exhibited reduced activity of cyclic nucleotide phosphodiesterases (PDEs), which hydrolyze cAMP and dampen the activation of the beta-adrenergic receptor signaling pathways. In this proposal, we will define the molecular basis of CnA-beta phosphatase in PDE s regulation in the beta-adrenergic receptor signaling pathways. The specific aims of this proposal are to examine: 1) The role of CnA-beta in the expression of PDE4D;and 2) The role of CnA-beta in the phosphorylation-dependent protein degradation. Completion of this proposal will provide better understanding of the calcineurin phosphatase, which is the main target of immunosuppressants cyclosporin A and tacrolimus. PUBLIC HEALTH RELEVANCE: Cyclosporin A and tacrolimus inhibit calcineurin and reduce graft rejection in transplanted patients, although these immunosuppressants can also elicit post- transplantation diabetes mellitus, hyperlipidemia and hypertension. Notably, lipid homeostasis and hemodynamic regulation are key physiological pathways regulated by the 2-adrenergic receptor signaling pathways. Defining the role of calcineurin in the 2- adrenergic receptor signaling pathways, therefore, will advance our knowledge of post- transplantation care.